Conformation pattern changes in R1-pS262 tau peptide induced endogenous tau aggregation, synaptic damage, and...

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• The precise impact of tau phosphorylation on protein conformation and function in Alzheimer's disease (AD) remains incompletely understood.
• Protein fingerprinting, or the protein folding shape code (PFSC) method, offers a sequence-based approach to predict protein spatial conformation.

Purpose of the Study:

• To elucidate the conformational effects of tau phosphorylation using PFSC technology.
• To analyze how phosphorylation at specific sites influences tau aggregation.

Main Methods:

• Conformational analysis of wild-type and mutant human tau (hTau441) via the PFSC method.
• Synthesis of phosphorylated and non-phosphorylated tau fragments using chemical solid-phase synthesis.

Main Results:

• Phosphorylation at Ser262 increased protein fingerprints, conformational changes, and flexibility.
• Phosphorylated tau fragments (R1-pS262) exhibited enhanced tau aggregation activity in vitro.
• R1-pS262 induced cognitive deficits, neuronal loss, and synaptic damage in a rat model.

Conclusions:

• Tau phosphorylation at Ser262 is a key driver of tau aggregation and subsequent neuropathological changes.
• This research provides novel insights into tauopathy pathogenesis and identifies a potential molecular target for intervention.